Benzyl-oxyalkyl and hydroxyalkyl



Patented Sept. 12, 1939 UNITED smite PATENT QFFIQE BENZYL-OXYALKYL ANDHYDROXYALKYL ETHERS OF CINCHONA'ALKALOIDS AND METHOD OF PREPARATIONCourtland L. Butler, Bennington, Vt., and Alice G. Renfrew and LeonardH. Cretcher, Pittsburgh, Pa., assignors to Mellon Institute ofIndustrial Research, a corporation of Pennsyl- Vania No Drawing.Original application April 26, 1937,

Serial No. 139,002. Divided and this application May 10, 1939, SerialNo. 272,854 7 '7 Claims.

This invention consists in new compositions of matter, benzyl-oxyalkyland hydroxyalkyl ethers of phenolic hydroXyl-group-oontaining cinchonaaikaloids, and in new processes for the hydroxyalkylation of thesealkaloids. This application is a division from an application filed bythese applicants April 26, 1937, Serial No. 139,002.

The method for the preparation of benzyl-oxyalkyl cinchona derivativesconsists in alkylation of phenolic hy-droxyl-group-c0ntaining cinchonaalkaloids with benzyl-oxyalkyl aromatic sulfonates according to theequation- CH V C JEC (H) R l l l l OHOH-C o 2 CH2 CHOHO +ArS 0 3K Ar =auaromatic radical R=-CI-I=CII2, :CHCHa, or OH2CH3 Hydroxyalkyl cinchonaethers are readily prepared from such benzyl oxyalkyl derivatives by HH: l CEOHCH CH2 CH2 These cinchona derivatives have valuable medicinalproperties and, in particular, find application as antip-neumococcicdrugs. We have reason to believe that they are very low in toxicity,that they are free of the damaging eye effect characteristic of somecinchona derivatives, and that they are highly active against thepneumococcus both in vitro and in vivo.

EXAMPLE l.-Allcylati0n of apocupreine with beneyl-oxyethyl benzenesulfonate 30 parts of apocupreine are converted to potassium salt inalcoholic solution, and digested for two hours on a water bath with 26parts of benzyl-oxyethyl benzene sulfonate. The reaction product,benzyl-oxyethyl apocupreine, is separated and worked up in the usualway. The substance may be conveniently recrystallized from acetone, ifdesired.

It will be understood that conversion to a potassium salt is exemplary;and that the conversion may be to any alkali salt, as a chemist knows.

EXAMPLE 2.Alkylation of dpoeupreine with benzyZ-omyethyl p-toluenesulfonate In a similar way 50 parts of apocupreine in the form ofpotassium salt are alkylated in alcoholic solution with 48 parts ofbenzyl-oxyethyl p-toluene sulfonate and the product, benzyl-oxyethylap-ocupreine, is separated and worked up.

EXAMPLE 3.-P reparati0n of benzyl-oxyethyl apocupreine fromB-chloroethyl apocuprez'ne B-chloroethyl apocupreine is prepared byalkylating the potassium salt of apocupreine with B- chloroethylp-toluene sulfonate.

90 parts of B-chloroethyl apocupreine are digested in benzyl alcoholsolution in which 6.5 parts of sodium has been dissolved. The reactionmixture is diluted with ether, and the solution is filtered from sodiumchloride. The desired product, benzyl-oxyethyl apocupreine, is eX-tracted from the ether solution with dilute sulfuric acid and worked upin the usual way.

EXAMPLE 4.Preparati0n of benzyZ-ozcyethyl hydrocupreine 90 parts ofhydrocupreine are converted to potassium salt in alcoholic solution andwarmed for two hours with 88 parts of benzyl-oxyethyl p-toluenesulionate. The desired product, benzyl-oxyethyl hydrocupreine, isseparated and worked up.

EXAMPLE 5.-Preparation of -r-benzyl-orcypropyl apocupreine 46 parts ofapocupreine in the form of potassium salt are alkylated in alcoholicsolution with 48 parts of T-bfiIlZYl-OXYQI'OPY-l p-toluene sulfonate.The desired product, 1-benzyloxypropyl apocupreine, is separated andworked up.

EXAMPLE 6.Prparation of I-benzyldmy Z-propyl apocupreine (or-methyls-benzylomyethyl apocupreine) 62 parts of apocupreine in the form ofpotassium salt are alkylated in alcoholic solution with 64 parts ofl-benzyloxy 2-propyl p-toluene sulfonate. The desired product,l-benzyloxy 2- propyl apocupreine, is separated and worked up.

EXAMPLE '7.Preparation of hydroxyethyl. apocupreine 9 parts ofbenzyl-oxyethyl apocupreine are dissolved in parts of dilutehydrochloric acid containing 16 parts of concentrated acid. Ondistillation the benzyl group is hydrolyzed off as benzyl chloride,which is carried over in the distillate. The last of the benzyl chlorideis removed by steam distillation. Hydroxyethyl apocupreine remains inthe acid solution in the reaction vessel. It is worked up in the usualway.

EXAMPLE 8.-Prepamtion of hydrowyethyl hydrocupreine In a similar waybenzyl-oxyethyl hydrocupreme is hydrolyzed in dilute hydrochloric acidto hydroxyethyl hydrocupreine and the product is separated and workedup.

EXAMPLE 9.Preparation of r-hydrowypropyl apocupreine r-benzyl-oxypropylapocupreine is similarly hydrolyzed in dilute acid and the product,whydroxypropyl apocupreine, is separated and worked EXAMPLE10.Preparation of I-hydroxy Z-propyl apocupreine (or-methyls-h'ydromyethyl apocupreine) l-benzyloxy 2-prop-yl apocupreine(oz-methyl pbenzyloxyethyl apocupreine) is similarly hydrolyzed indilute hydrochloric acid and the product, l-hydroxy 2-propylapocupreine, is separated and worked up.

In the same natural class with the products of Examples 9 and 10 liese-hydroxypropyl apocupreine of the formula- These three compounds fallinto the natural class of isomeric hydroxy propyl ethers, where thehydroxyl is on a carbon atom other than that attached to the etheroxygen atom.

We claim as our invention: 1. As a new composition of matter, a hydroxypropyl apo-cupreine of empirical formula,

2. The method herein described of preparing a hydroxyalkyl ether of acinchona alkaloid, which consists in preparing a benzyloxyalkyl ether ofa phenolic-hydroxyl-group containing cinchona alkaloid as hereindescribed, hydrolyzing the benzyloxyalkyl ether thus prepared in dilutehydrochloric acid to a hydroxyalkyl ether, and isolating the desiredproduct.

3. As a new composition of matter, r-hydroxypropyl apocupreine, offormula as specified.

4. The method herein described of preparing hydroxyethyl apocupreinewhich consists in hydrolyzing benzyl-oxyethyl apocupreine in dilutehydrochloric acid, and separating and working up the product.

5. As a new composition, l-hydroxy 2-propyl apocupreine (or-methylp-hydroxyethyl apocupreine) of formula HOCHZCH -OCHHMONI

